Abstract

The MYC transcription factor, together with its obligate dimerization partner, MAX, regulates widespread gene expression and is implicated in the etiology of a broad spectrum of cancers. MYC and MAX are members of the MAX-MLX superfamily of bHLHZ transcription factors (which includes MYC, MAX, MXD, MLX, and MONDO/ChREBP). Members of this highly conserved family respond to environmental cues to modulate gene expression programs and control cellular fate. We recently showed that metabolic reprogramming and survival in MYC-driven cancer cells is coordinately regulated by MYC-MAX and MONDOA-MLX. While knockdown of MONDOA or MLX affected multiple metabolic pathways in MYC-induced tumors, we found that decreased fatty acid synthesis primarily accounted for the loss of viability (Carroll et al. Cancer Cell 27:271, 2015)

To explore the physiological role of the MLX branch of the MAX-MLX network we generated mice with targeted deletion of Mlx. Mlx null mice appeared to develop normally; however, we found that Mlx null males are infertile, with strikingly diminished sperm production, viability, and motility. MondoA knockout mice exhibited a similar phenotype. By employing tissue-specific Cre-mediated deletion of Mlx, we uncovered metabolic defects in both Sertoli cells as well as germ cells, including loss of lipogenic enzymes and altered lipid content. Moreover, we found that human male germ cell tumors (MGCTs) overexpress MAX-MLX network proteins and undergo apoptosis upon loss of MONDOA/MLX. Importantly, the same metabolic pathways shown to be crucial for survival of neuroblastoma are also required for survival of MGCTs.

Furthermore. we have uncovered a critical role for MLX in myokine production required for myoblast fusion in vitro. Moreover, mice bearing homozygous deletion of Mlx fail to regenerate muscle following cardiotoxin treatment (Hunt et al. Genes Dev. 29:2475, 2015). Taken together, our studies suggest a critical role for the MLX arm of the MAX-MLX network in adaptive metabolic responses in tumorigenesis and development.

Funding: NIH grants CA57138 (to RNE) and GM055668 (to DEA); ALSAC of St. Jude Children's Research Hospital, the Ellison Medical Foundation, the Glenn Foundation for Medical Research, and the American Federation for Aging Research (AFAR) (to FD).